系统生物 第一章 概述学习资料

第一章概述诱导多功能干细胞随机模型Totipotentfertilizedeggsdifferentiateintovariouslineagesthroughthepluripotentstatus.HereIdepictthisprocessinthecontextoftheepigeneticlandscapeproposedbyConradWaddington26.TheiPScellislikeaballrollingdowntheslopeofavalley.Thereprogrammingfactorscooperativelypushcellsuptheslopetothepluripotentzone.Somecellsareblockedbyanepigeneticbump(closedrectangle)ontheslopeandthusbecomeabletoself-renew(1).Othercellsareonlypartiallyreprogrammedandarenotblockedbythebump;therefore,withouttheexogenousreprogrammingfactors,theywouldrolldownagain(2).Whentheexpressionofthereprogrammingfactorsisnotappropriate,cellsmaytransformtoothertypesofcell,orevenundergoapoptosisorsenescence.Forcellsthatarelocatedonthemiddleofthevalley(thatis,somaticstemcells)itmightbeeasiertogobacktothepluripotentstate.(Inthestochasticmodel,most,ifnotall,differentiatedcellshavethepotentialtobecomeiPScellsaftertheintroductionofthefourfactors.Celldifferentiationisoftendescribedasaballrollingdownanepigeneticlandscape,firstdepictedbyConradWaddingtonin1957,startingfromthetotipotentstate,goingthroughthepluripotentstate,androllingdowntoalineage-committedstate26(Fig.2).Innormaldevelopment,pluripotentcellsappeartransiently.Theycannotstopontheslopeandarepulledbygravitytorapidlydifferentiateintovariouslineages.Incontrast,EScellscanself-renewandmaintainpluripotencyforalongtime.Thus,itisasifEScellsareblockedbyabumporaroadblockformedbytheirparticularepigeneticstatus.Inthismetaphor,thefourreprogrammingfactorscooperativelypushthecellsupintothepluripotentstate.(Inthestochasticmodel,most,ifnotall,differentiatedcellshavethepotentialtobecomeiPScellsaftertheintroductionofthefourfactors.Celldifferentiationisoftendescribedasaballrollingdownanepigeneticlandscape,firstdepictedbyConradWaddingtonin1957,startingfromthetotipotentstate,goingthroughthepluripotentstate,androllingdowntoalineage-committedstate26(Fig.2).Innormaldevelopment,pluripotentcellsappeartransiently.Theycannotstopontheslopeandarepulledbygravitytorapidlydifferentiateintovariouslineages.Incontrast,EScellscanself-renewandmaintainpluripotencyforalongtime.Thus,itisasifEScellsareblockedbyabumporaroadblockformedbytheirparticularepigeneticstatus.Inthismetaphor,thefourreprogrammingfactorscooperativelypushthecellsupintothepluripotentstate.Thereareatleasttworequirementsforcompletereprogramming.First,thefourfactorsmustbeexpressedinapatternthatprovidesasufficientpushintherightdirection.Becauseavailabletechnologiescannotpreciselycontroltheexpressionlevelsofthefourtransgenes,thisfirstrequirementcanonlybeachievedstochastically.Second,cellsmustbeblockedbytheepigeneticbumpsothattheycanremaininthepluripotentzoneevenwhenthetransgeneexpressiondisappears.Becausethefourreprogrammingfactorsalonecannotconstitutesuchanepigeneticroadblock,stochasticeventsagainarerequiredduringiPScellgeneration.Ashasbeendemonstratedinreprogrammingbynucleartransfer,DNAmethylationandhistonemodificationsprobablyhaveimportantrolesiniPScellgeneration.)细胞自动机是一种离散模型，在可算性理论、数学及理论生物学都有相关研究。它是由无限个有规律、坚硬的方格组成，每格均处于一种有限状态。整个格网可以是任何有限维的。同时也是离散的。每格于t时的态由t-1时的一集有限格（这集叫那格的邻域）的态决定。每一格的“邻居”都是已被固定的。（一格可以是自己的邻居。）每次演进时，每格均遵从同一规矩一齐演进。细胞自动机有三个特征：平行计算（parallelcomputation）：每一个细胞个体都同时同步的改变局部的（local）：细胞的状态变化只受周遭细胞的影响。一致性的（homogeneous）：所有细胞均受同样的规则所支配Thesimplestnontrivialcellularautomatonwouldbeone-dimensional,withtwopossiblestatespercell,andacell'sneighborsdefinedtobetheadjacentcellsoneithersideofit.Acellanditstwoneighborsformaneighborhoodof3cells,sothereare23=8possiblepatternsforaneighborhood.Aruleconsistsofdeciding,foreachpattern,whetherthecellwillbea1ora0inthenextgeneration.Therearethen28=256possiblerules.ProtnetThegraphinpanelAisbasedonthehighconfidenceinteractomethatwasusedasinputinoursimulations.Pinkspheresrepresentproteinsthat,attheendof50000steps,werenotfoundtobeinvolvedintheformationofanycomplexinaspecificsimulationrun.Largehighlyconnectedprotein"clusters"thatcanbemappedtophysiologicallyrelevantcomplexesareoutlinedwithabrownbackgroundandidentified.InpanelBwehavefilteredtheinputgraph(panelA)byeliminatingtheedgesrepresentinginteractionsinwhichthepartnerproteinsarefoundlessthan10%ofthetimes.Catastrophetheory突变理论从牛顿和G.W.莱布尼兹时代以来得到很大发展的微积分学，一般只考虑光滑的连续变化的过程，而突变论则研究跳跃式转变、不连续过程和突发的质变。突变论的基础是结构稳定性。结构稳定性反映同种物体在形态上千差万别中的相似性。例如，人的面貌虽因岁月流逝而发生变化，但仍存在区别于他人的特征。结构稳定的丧失，就是突变的开始。突变论的创始人是法国数学家雷内托姆，他于1972年发表的《结构稳定性和形态发生学》一书阐述了突变理论，荣获国际数学界的最高奖菲尔兹奖章。突变论的出现引起各方面的重视，被称之为“是牛顿和莱布尼茨发明微积分三百年以来数学上最大的革命”。MassivegenomicrearrangementacquiredinaSingleCatastrophicEventduringCancerDevelopmentCancerisdrivenbysomaticallyacquiredpointmutationsandchromosomalrearrangements,conventionallythoughttoaccumulategraduallyovertime.Usingnext-generationsequencing,wecharacterizeaphenomenon,whichwetermchromothripsis,wherebytenstohundredsofgenomicrearrangementsoccurinaone-offcellularcrisis.Rearrangementsinvolvingoneorafewchromosomescrisscrossbackandforthacrossinvolvedregions,generatingfrequentoscillationsbetweentwocopynumberstates.Thesegenomichallmarksarehighlyimprobableifrearrangementsaccumulateovertimeandinsteadimplythatnearlyalloccurduringasinglecellularcatastrophe.Thestampofchromothripsiscanbeseeninatleast2%–3%ofallcancers,acrossmanysubtypes,andispresentin25%ofbonecancers.Wefindthatone,orindeedmorethanone,cancer-causinglesioncanemergeoutofthegenomiccrisis.Thisphenomenonhasimportantimplicationsfortheoriginsofgenomicremodelingandtemporalemergenceofcancer.分级系统ageneraltheoryfortheoptimisationoftwo-levelhierarchicalsystemshasbeenintroduced.Thistheorycanbeappliedonawiderangeofapplications,examplesbeingeconomics,organisationtheoryandlargescaleindustrialplants.Inthistheorythesystemisdividedintosub-systems,whereeachsub-systemtriestoachieveitsownobjectiveswithoutconsideringwhetherornottheycontradictwithothersub-systems.Inordertorectifythe’selfishness’ofthesub-systemdecisionmaking,anupper-leveldecisionmakingsystemhastobeintroduced.Theobjectiveoftheupper-leveldecisionmakingunitistocoordinatethedecisionmakingofeachsub-system,sothatanoverallharmonyisachieved.Aspecialemphasiswasputonthesocalledbalancingtechnique,becauseitcanbeimplementednumericallywiththewell-knownLangrangetechnique.Notethatinthisreportnorigorousconvergencetheorywaspresentedfortheiterativebalancingtechnique.Adiagramofastandardtwo-levelhierarchicalsystemisshowninFig.12.1,where,asexpected,twolevelscanbefound,namelythelowerlevelandtheupperlevel.Thelowerlevelconsistsoftheprocesslevel,wheretheprocesslevelhasbeendividedintoNsub-systems.Thesub-systemsareconnectedtoeachotherbecausethereiseithermaterialorinformationflowsbetweenthesesub-systems.Eachsub-systemhasitsowndecisionunit,whichtriestocontrolthebehaviourofthesub-systemsothattheobjectivesofthisparticularsub-systemwouldbemet.Thedecisionunitcanalsousefeedbackinformationfromthesub-systemtoimproveits’controlpolicy’.However,quiteoftentheobjectivesofthesub-systemsareconflicting,resultinginapooroverallperformance.Henceanupper-leveldecisionunitoracoordinatorhastobeintroduced,andtheobjectiveofthisdecisionunitistocoordinatethedecisionmakingofthesub-systemssothattheoverallperformanceofthesystemwouldbeimproved.Thecoordinatorreceivesinformationfromthesub-systemssothatitcanmonitortheperformanceoftheoverallsystem.Notethatthisapproachisnotasrestrictiveasitsounds,becauseifanewhigherlevelisaddedintoatwo-levelsystem,inmostofcasesthenewlevelcanbechosentobethehigherlevelofthemodifiedsystem,andtheoriginaltwo-levelsystembecomesthelower-levelofthemodifiedsystem.OscillationsinNF-kBSignalingControltheDynamicsofGeneExpressionNF-kBSignaling的震动控制基因表达动力学SignalingbythetranscriptionfactornuclearfactorkappaB(NF-.B)involvesitsreleasefrominhibitorkappaB(I.B)inthecytosol,followedbytranslocationintothenucleus.NF-.BregulationofI.B!transcriptionrepresentsadelayednegativefeedbackloopthatdrivesoscillationsinNF-.Btranslocation.Singlecelltime-lapseimagingandcomputationalmodelingofNF-.B(RelA)localizationshowedasynchronousoscillationsfollowingcellstimulationthatdecreasedinfrequencywithincreasedI.B!transcription.Transcriptionoftargetgenesdependedonoscillationpersistence,involvingcyclesofRelAphosphorylationanddephosphorylation.ThefunctionalconsequencesofNF-.Bsignalingmaythusdependonnumber,period,andamplitudeofoscillations.1-50.例如，为了从表达谱推导基因调控网络，需要全面测量基因表达谱。野生型的表达数据往往难以满足要求。它需要每个基因缺失突变和过表达所产生的完整数据集。所有敲除基因的数据集使用基因芯片测量。如果因为价格或时间的限制，仅仅有限个基因被敲除，那么敲除紧密关联的基因比在整个调控网络上稀疏地敲除一些基因要好的多。稀疏数据点给可能的网络结构留下了很多不确定因素。即使是使用相同数量的数据，测量密切相关的基因所产生的网络也较上述方法更可靠。这就是要素完备性。1-51时序完备性则对时序现象是必须的。时间序列数据需要特别谨慎，保证样本同步测量。在传统生物学实验中往往是这样的情况：只有两个测量点，一个在事件前，一个在事件后。例如，许多关于细胞衰老的研究测量年轻细胞、年老细胞以及永生细胞的衰老相关的基因表达，而不按精细的时间序列来记录表达水平的变化。很多情况下，表达水平随时间的变化对于提出或否定假设可能是十分重要的。除了需要在感兴趣的生物学时间前后测量外，还必须进行固定时间间隔的采样测量。具有可靠的采样时间同步性和恒定的时间间隔的表达谱数据对计算算法拟合模型、参数与实验数据十分有益。1-52来自蛋白质之间相互作用的信息，譬如酵母双杂交实验，对推导蛋白质水平的交互，从而填补基因调控研究的空白就十分有用。1-53这一点就是说并非系统的所有部分必须使用相同的准确度。例如喷气式引擎的组件需要高准确度，但是座椅绑带显然就无须和引擎同样的精度。在未来的研究中，实验的类型以及准确度要求可以通过理论条件来确定。1-55蛋白质相互作用及表达谱必须在相同制备的样本上进行测量。这个系统测量的要求现在是非常难以满足的，因为很少有研究组可以提供多种测量技术。线虫C.elegansisaveryfamousorganisminthefieldoflifescience.Since1998itswholegenomehasbeensuccessfullysequenced,thereare5scientistswintheNobelPrizesbecauseoftheirworkonC.elegans.Therecanbe4vocabulariesdescribingthissmartanimal,simple,open,cleverandcorrelative.Itissimple:itis1mminlengthandabout50micrometerindiameter.Thewholebodyiscomposedofonlyseveralthousandsofcells.Itisveryopen:Itisbisexual,andthebodyistotallytransparent.Wecanidentifyeachcellunderthemicroscope.Itisclever:Itcanhavesensitiveresponsestoenvironmentalchangesandlearnsomething.Itiscorrelative,because40%ofgenomeissimilartohumanbeing,andover70%genescouldbeidentifiedtheircounterpartanaloguesinotheranimals.So,itiscurrentlythemodelspeciesingenetics,neuroscienceanddevelopmentalbiology.1-59如果该项目成功的话，就可以用于早期胚胎发生时所有RNAi敲除后细胞系的自动鉴定。随着不断的努力，这些技术的增强将用于细胞之间接触、蛋白质定位等的自动检测。结合整体原位杂交和将来可能进行的单细胞表达谱，基因调控网络的完全鉴定在不久的将来将成为可能1-69SimplifiedversionofthephageldecisioncircuitthatdetermineswhetherinfectedEscherichiacolicellsfollowthelyticorlysogenicpathway.Boldhorizontallinesindicatestretchesofdouble-strandedDNA.Arrowsingenesindicatethedirectionoftranscription.TheboxesR1–R3indicatenon-geneticproteinreactionsubsystems.Thethreeoperatorsites,OR1–R3,ofthe‘lswitch’implementaconcentration-dependent‘logic’,controllingpromotersPRMandPR.CroandCIdimersbindtothethreesiteswithdifferentaffinitiesandinoppositeordertocontroltheactivationlevelofthePRMandPRpromoters40,41.TheCIdimeractsaseitherarepressororactivatorofpromoterPRM,dependingonitsconcentration.Theresultisamutuallyexclusivelockingmechanism,sothateitherPRMorPRendsupbeingactivatedwiththeotherpromoterlockedoff.StrongproductionofCIrelativelysoonafterinfectionisnecessaryforlockingonthePRMlooptoselectthelysogenicpathway.ThisoccursonlywhenthestrongpromoterPREisactivatedbyCIIto‘jumpstart’CIproduction.DegradationofCIIisinhibitedbyCIII,soproductionofCIIIincreasestheprobabilityofCI‘winning’therace.EnvironmentalsignalsinfluencetheoutcomebyaffectingtherateofCIIdegradation.Duetothestochasticcharacterofproteinproductionandtheotherreactionsinvolved,boththelyticandthelysogenicoutcomecanoccurwithsomeprobability,sothattwoalternativephenotypesresult.1-73如何改变自身以适应环境的变化？如何消除DNA损伤和突变对系统的潜在影响以维持稳定？特定回路如何展示出观察到的功能？为了获得系统层次的理解，需要理解系统鲁棒性、稳定性和回路功能性背后的机制。1-74基因与代谢网络行为的仿真在系统生物学研究中扮演着重要的角色，仿真不仅仅是理解系统行为的基本工具，而且是设计过程的基本工具。仿真是生物系统研究的可行方法，因此需要开发高实用化、精确、用户界面友好的仿真系统。仿真系统需要与参数优化工具、假设生成器以及分析工具结合，然而这些软件后面的算法需要针对生物学研究精确设计1-75系统生物学研究需要开发和整合一系列软件系统，包括：存储实验数据的数据库细胞与组织仿真系统参数优化软件分叉和系统分析软件假设生成器和实验设计专家系统数据可视化软件1-79来自复杂工程系统的经验在工程系统与生物系统之间有很多有趣的相似之处：二者都通过一些进化过程来增量设计对给定的问题一般获得次优解为了获得更高的鲁棒性和稳定性，系统复杂度也随之递增。1-81前馈控制中预定义了一系列受特定刺激触发的动作，是一种开环而且简单的系统，仅仅在可能情形与对策都高度可预见的情况下使用。反馈控制，如负反馈控制，广泛应用于工程中。它将期望值和实际值之间的误差取负后反馈给输入，使输入信号受到正比于误差的调整。其基本形式中，表现为最小化输出误差值的效果。反馈在生物过程中的很多方面扮演着重要角色，如大肠杆菌的趋化性和热休克响应、生理节律、细胞周期以及发育的各个方面。1-82最典型的例子是细菌趋化性中的整体反馈回路。细菌表现出对很大浓度范围下化学试剂的适应性，因此可以感知化学浓度变化来决定其行为。这是通过一个包含闭环反馈的回路实现的。如图所示，趋化性中的配体和特定的受体MCP结合形成了包含CheA和CheW的稳定复合体。CheA磷酸化CheB及CheY。磷酸化的CheB使MCP复合体去甲基化，磷酸化的CheY触发紊乱行为。实验和仿真都表明这形成了一个反馈回路从而适应配体浓度变化。特别是对配体浓度的突然变化，通过紊乱频率来表征的平均活动水平可以迅速收敛到一稳态值。这意味着系统仅仅可以探测到决定紊乱频率的配体浓度的变化，而对浓度绝对值不敏感。因此，不管绝对浓度